Dr. Urano’s November Update

November 4, 2017Fumihiko “Fumi” Urano, MD

Dear Friends,

It has been a while since we last talked. I hope you are enjoying this Fall season with your family and friends. I think about the value of family and friends a lot lately. Support from family and friends keeps me going. So I appreciate your continued support, encouragement, and kind words. Let me update your about our progress on therapeutic development for Wolfram syndrome.

Our drug-repurposing clinical trial of dantrolene sodium is ongoing. The trial began in January, and nineteen patients with Wolfram syndrome from the US and Canada are now involved. Participation requires periodic testing and monitoring at the adult and pediatric clinics at Washington University Medical Center in St. Louis.  The trial is focused on the safety, tolerability, and efficacy of the drug (visual acuity, neurological functions and remaining beta cell functions). At this stage my team has found few side effects and has identified safe dosage levels. More tests and data are necessary before any conclusions can be reached.

I am aware that we need a breakthrough therapy for Wolfram syndrome. In theory, drugs that target endoplasmic reticulum (a cellular compartment damaged in Wolfram patients), such as dantrolene sodium, can delay the progression and may improve functions of remaining beta cells and brain cells, but these drugs cannot reverse symptoms. We need something that can reverse symptoms, such as visual impairment, and we need to tap into new technologies. We are developing a regenerative gene therapy, especially for visual impairment. Our strategy is to introduce a regeneration factor into a type of retinal cells using a gene transfer technology. This is clearly not simple and requires a lot of time and efforts, but we are making progress.

Thank you for taking your time to read my blog. I hope to talk to you again soon.

Warmest regards,
Fumi Urano, MD

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A British Consortium wins the joint call for proposals

Three British and one Australian research teams, coordinated by Professor Timothy Barrett, have been awarded the funding of 200,000 € by the Association syndrome de Wolfram, the Eye Hope Foundation and the Snow Foundation. Their project aims at “developing biomarkers that will show early evidence of benefit of a treatment; and patient self-report outcome measures that will help with regulatory approval. These two initiatives will speed up the delivery of treatments to patients in the clinic”.

British Consortium - Association for Wolfram Syndrome + Eye Hope Foundation + The Snow Foundation logos

On April 25th 2017, the Association syndrome de Wolfram (France), the Eye Hope Foundation (Belgium) and the Snow Foundation (USA) have decided to join forces to more efficiently fight the disease. Their objective: fund a large-scale project aimed at accelerating the development of new treatments against Wolfram syndrome.

They organized a call for proposals, which was a great success. Six research teams, located in six different countries (USA, Belgium, France, United-Kingdom, Spain and Israel), have sent a proposal. These proposals were then evaluated by a pool of independent world-renowned experts in the field of Wolfram syndrome and drug development. Based on their recommendations, the Presidents of the three organizations have elected the most promising project.
The project coordinated by Professor Timothy Barrett is entitled “Accelerating clinical trials in Wolfram syndrome: development of efficacy biomarkers and patient relevant outcome measures”. It will start on October 1st 2017 and will terminate by September 2019. It is funded through equal contributions from the Association syndrome de Wolfram (France), the Eye Hope Foundation (Belgium) and the Snow Foundation (USA).

A note from Dr. Timothy Barrett

“The international Wolfram community stands out from other rare disease communities in that it is highly collaborative: research scientists and patient groups work closely together across academic institution and national boundaries. The initiative by Association Syndrome de Wolfram, Eye Hope Foundation, and The Snow Foundation, is an outstanding example of this. Our teams are highly honored to be awarded the first joint funding, and we will work hard to ensure our research leads to benefits for patients. We will address one of the blocks to treatments, by finding ways to measure their effects on outcomes important for patients. At the end of our studies, we will have a toolbox of markers to show when treatments work, and to help convince health regulators to license treatments for patients to use in the clinic.”

Sincerely,

Tim Barrett

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Dr. Urano’s September update

September 22, 2017Fumihiko “Fumi” Urano, MD

Dear Friends,

It is nice to “meet” you again. Thank you for your generous and continued support for our therapeutic development for Wolfram syndrome. With the support from the Snow Foundation, multiple patient organizations and supporters around the world, and federal grants, I could maintain the Wolfram syndrome program to study the disease, which led to fundamental laboratory studies that uncovered the molecular genetic defect, and ultimately to the identification of a therapeutic target that is now being tested in patients. Our first clinical trial of a re-purposed drug, dantrolene sodium, in patients with Wolfram syndrome is ongoing. We have been monitoring the safety, tolerability, and efficacy of dantrolene sodium in 21 patients who have qualified for the study. You can find the information about the inclusion and exclusion criteria on the following website. We have both male and female participants in pediatric and adult populations. https://clinicaltrials.gov/ct2/show/NCT028292680

The planned duration of oral dantrolene sodium administration in this study is 6 months with an optional extension phase up to 24 month. All the participants are required to come to our clinic 9 times in the first 6 months to determine the appropriate dose and ensure the safety. After the first 6 months, participants come to our clinic every 6 months up to 24 months. As of today (September 22, 2017), 20 participants are taking dantrolene sodium and one participant has left the study due to personal reasons. 9 out of 20 patients have been taking dantrolene sodium for more than 6 months. In addition to safety and tolerability, we have been assessing our participants’ visual acuity, remaining beta cell functions (i.e., their ability to produce insulin from their own pancreases), and neurological functions every 6 months. We plan to publish the data once we collect the information from these 20 participants after the 6-month administration of dantrolene sodium.

On a different note, Senator Roy Blunt and the Director of National Center for Advancing Translational Sciences (NCATS), Dr. Christopher Austin (https://ncats.nih.gov/), visited our medical center last month. I had a chance to present our medical center’s efforts on rare disease therapies. I am glad to tell you that our presentations were perceived really well. Stephanie and I met with Dr. Austin a few years ago at the NCATS headquarter in Bethesda, close to Washington DC, and that was the beginning of my collaboration with the drug development team at NCATS. We will keep on working together for developing rare disease therapies.

Thank you for being with me. I plan to update you about our two new drugs and regenerative gene therapy for retinal degeneration in my next blog. I hope you will have a wonderful fall season. See you soon.

Warmest regards,
Fumi Urano, MD

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Dr. Urano’s August update

Fumihiko “Fumi” Urano, MD

Dr. Fumihiko “Fumi” Urano, MD

Dear Friends,

I hope you had a wonderful summer season. I would like to update you about our progress.

Our clinical trial of dantrolene sodium in patients with Wolfram syndrome is ongoing. We have been monitoring the safety, tolerability, and efficacy of the drug. Some patients have been taking dantrolene sodium for more than 6 months, and we have started getting the safety, tolerability, and efficacy data. We plan to publish the data once we collect the information from 20 patients. I have started preparing for the next phase of this trial. As I mentioned in my previous blog, we are considering the following possibilities.

  1. A longer duration, More participants, Multi-center
  2. Include the placebo arm. I understand that nobody wants to take the dummy drug for a long period of time. So I have been getting advice from medical officers conducting clinical trials for rare diseases.

In addition to dantrolene sodium, my team has been looking into two new drugs for Wolfram. Unlike dantrolene sodium, these drugs are new. So we need to carefully collect more data from mouse models of Wolfram and healthy human subjects.

  1. The first drug is an endoplasmic reticulum (ER) calcium stabilizers which we discovered together with NIH/NCATS. This drug is for delaying/halting the progression of the disease. Pre-clinical studies in mouse models of Wolfram are ongoing.
  2. The second drug is a chemical chaperone which reduces ER stress. We have started collaboration with a biotech company on this new drug.

I am aware that we need to find a way to improve visual acuity. I am trying to secure funds for testing our new regenerative gene therapies for optic nerve degeneration using a novel neurotrophic factor in combination with gene transfer technology. I have applied for multiple grants and am quite hopeful about the outcome.

Thank you for your continued support. I cannot thank you enough.

Take care,

Fumi Urano, MD

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Washington University Wolfram Research Clinic completes its 8th consecutive year!

Washington-University-School-of-MedicineWashington-University-Wolfram-Study-group

Dear Wolfram Families and Supporters:

The Washington University Wolfram Research Clinic (or ‘natural history) study just finished its 8th consecutive year of assessing patients with Wolfram Syndrome. This work began in 2010, supported in part by the Snow Foundation. For the past 5 years, it has been supported by a National Institutes of Health grant in Dr. Hershey’s lab (Tracking Neurodegeneration in Wolfram Syndrome; Hershey, Principal Investigator). The focus of this grant is on understanding the neurological changes that may occur over time in Wolfram Syndrome, including the function of the brain (e.g. vision, balance) and the structure of the brain (e.g. the volume or integrity of different regions of the brain).

This year, we focused on assessing new patients, and those who had only been seen once or twice before. We hosted 9 families from all over the country and performed 106 exams and 8 MRIs. This clinic was smaller than previous years due to limitations in funding and the ongoing Dantrolene safety study. However, this focus allowed us to increase our understanding of how symptoms change over a 2 year time period, which are critical data for planning and implementing clinical trials. Altogether, over the past 8 years, we have assessed 40 unique individuals with Wolfram Syndrome and their families, some up to 7 times.

Just weeks before the clinic, we got the good news that our request to extend this work for another 5 years was reviewed very favorably! We received a score which should ensure that we get the funding we need, but will only know for sure this fall. In anticipation, we are going to start planning for next summer’s research clinic soon and hope to open it to anyone who has been seen in the past or any new patients that come to our attention. We will work together with Dr. Urano on any ongoing drug safety or efficacy studies to make sure that families do not have to choose between studies and that each study can support the other’s goals. 

As always, we will keep you up to date with our WU Wolfram Research Clinic newsletters, the Snow Foundation newsletters, our website (http://hersheylab.wustl.edu) and emails or calls. Please contact any of us at any time if we can provide more information or assistance!  We would love to hear from you!

Thank you!

Tamara Hershey, Ph. D.

Professor & Principal Investigator,
WU Wolfram Research Clinic

314 362-5593

tammy@wustl.edu

Bess Marshall, MD

Pediatric Endocrinologist & Research Clinic Medical Director

314 454-6051
Marshall@kids.wustl.edu

Samantha Ranck, MSW

Research Clinic Coordinator

314 362-6514
rancks@npg.wustl.edu

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TreatWolfram Clinical Trial update – June

Dear Friends and colleagues,

I would like to give you an update as to progress with our clinical trial of a treatment for Wolfram syndrome.

We had the final confirmation of funding from the UK Medical Research Council on December 16th 2016, so were able to start work on the study protocol early in the New Year. We were fortunate to have Ms Rebecca Storey appointed as Senior Trials Coordinator in January. She has lots of experience in running clinical trials, and is based in the Clinical Trials Unit, University of Birmingham. She hopes to attend the family conference in October, so I hope some of you will meet her.

We then appointed local lead investigators for the UK: this will be Dr Renuka Dias for the children’s hospital clinic, and Dr Ben Wright for the Queen Elizabeth Hospital adult clinic. Also in January, Tracy kindly met with me at my parents’ house near Gatwick Airport, where we discussed what the clinical trial would look like, and what to include in the participant information sheets. The main point was that families would prefer partipants to have an increased chance of receiving the study medicine rather than the placebo. I took this back to our trial statistician Kristian Brock, who has been able to include this request. Participants will now have a 2:1 chance of being given the study medicine rather than the placebo. Kristian Brock is an expert in statistics and trial design, and will also try to attend the family conference.

In February we started discussions with Guy’s and Thomas’s Pharmacy manufacturing unit to prepare the medicine and placebo. We also prepared the ethics application form, and had a telephone conference with our international partners in Spain, France and Poland.

In March I went to our local Young Persons’ Advisory Group. This is a group of 11-23 year olds, who kindly volunteer to read study information and critically appraise it so that it is readable and easily understood. I took them the participant information sheets I had prepared, and I am sorry to say they looked them over very critically! They pointed out that the layout could be improved; that there was some repetition; and that a glossary of medical terms would help. I am very grateful to them and the information sheets are now shorter and clearer to read.

In April I attended the European Medicines Agency in London with Julie Warner, from Boyd Consultants, who provide regulatory advice. They agreed that we must check if the treatment slows the rate of deterioration of vision; however they would like a second outcome measure that is important for families. We are now working with experts on patient reported outcome measures, and would like to propose some ideas to you – things to measure which are important for a treatment to improve.

I also visited the French Wolfram association in Paris, just before Easter, and attempted to present the clinical trial in French. The audience was very polite and tolerated my schoolboy French! In May I gave a similar presentation to Spanish families in Almeria, hosted by Dr Gema Esteban, our Spanish collaborator. There is a lot of enthusiasm to take part, and there were many questions. Some of these related to randomisation, and I had to explain that the European Medicines Agency insist that some people receive the medicine and some the placebo. This is in order to provide the strongest evidence that our medicine works.

We are now hoping to sign the contract with the pharmacy manufacturers; submit the ethics application package in September; and recruit the first participants in the UK at the end of November. The timescale has been extended as we have to show that the medicine is stable outside the manufacturer’s packaging, when we put it in airtight plastic containers. This stability testing started last week, and takes 3 months.

Later this month, we have a local investigator meeting, where we will sort out the practical aspects of what tests we will be asking participants to have. I would like to write another update at the beginning of July when I can feed back on this meeting.

Please don’t hesitate to get in contact if I can help at all with any questions. Meantime, thankyou all for your kind interest and support!

Sincerely

Prof Tim Barrett

Dr. Urano’s June Wolfram Research Update

Fumihiko “Fumi” Urano, MDDear Friends,

It’s a spectacular Saturday morning in Saint Louis as I write this to you. I always appreciate your continued support, encouragement, and kind words.

I have received many questions regarding our ongoing clinical trial, as well as questions related to our next step lately.

Although we don’t have a concrete plan yet, we consider the following possibilities.

  1. A longer duration, More participants, Multi-center
  2. Compare the efficacy of dantrolene sodium, valproic acid, and dantrolene sodium plus valproic acid

We are also developing breakthrough treatments for Wolfram syndrome as dantrolene and valporic acid are old drugs originally developed for other medical conditions.

Here are our new plans.

  1. We have been developing a new drug designed for Wolfram syndrome  (ER stress stabilizers) together with NIH/NCATS to delay/halt the progression of the disease. Pre-clinical studies in mouse models of Wolfram have been designed. We are seeking funds to complete these studies.
  2. Regenerative therapies using a novel neurotrophic factor in combination with gene transfer technology for visual impairment have been designed. We are seeking funds for testing these new therapies in mouse models of Wolfram syndrome.

I think we are making progress, and need to speed up as we are racing against time. Thank you again for your support.

Take care,

Fumi Urano, MD

Dr. Barrett meets with Wolfram Associations across the globe

Dear Friends and colleagues,

I have been fortunate to visit the French Wolfram Association meeting in April in Paris; and the Spanish Wolfram association meeting in May in Almeria.

I was humbled by the friendship and community spirit of these families; and they were very tolerant of my poor French and Spanish language skills.

On the research front, we have just published the online mutation database of genetic variants in the Wolfram gene. This was work undertaken by Dr Dewi Astuti, and is a freely available database to support scientists worldwide. The database is available at: https://lovd.euro-wabb.org

Regarding the Phase II clinical trial, we are negotiating manufacture of the investigational medicinal product and placebo. We hope to complete this in the next 4 weeks and are still aiming to begin recruitment in the UK in November.

Thank you for all your interest and support, and I will try to provide regular updates on our progress

Sincerely,

Prof Tim Barrett

Research update letter about treatment studies in Wolfram Syndrome

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Clinical Trial Update by Fumihiko Urano, M.D.

Dear Friends,

I would like to update you about the status of our clinical trial of dantrolene sodium in patients with Wolfram syndrome. Dantrolene is a US Food and Drug Administration (FDA)-approved drug currently used for different medical conditions. Based on our data, we received orphan drug designation of dantrolene sodium for the treatment of Wolfram syndrome from US FDA and European Medicines Agency (EMA) in 2016. We also ​received the​ green light from ​the ​FDA and Washington University Medical Center to proceed to a pilot clinical trial (phase 1b) to assess the safety and efficacy of dantrolene on patient’s vision, brain functions, and diabetes.

Thanks to the generous support from the Snow Foundation in collaboration with Ellie White Foundation and other private donors, I was able to commence the clinical trial and slowly started recruiting patients. I would like to recruit at least 24 patients and hope to secure more funds to accommodate all the patients who are eligible for this trial. Stephanie Gebel​ has told me that she will do her best to make this happen. ​I was just informed ​​this week that we will receive grant funding from the National Institutes of Health (NIH) to support this trial.

​have not forgotten​ about our patients in other countries. Dr. Tim Barrett in the UK and I are closely working ​to conduct international clinical trials for Wolfram syndrome. In parallel, we keep on developing novel drugs and regenerative therapies for Wolfram syndrome. Dantrolene could be a band-aid for Wolfram, but cannot provide a cure. Thus, we need pipelines for developing breakthrough treatments.

Thank you for your continued support.

Sincerely,

Fumi Urano, MD